CN106062564A - A method for quantifying an analyte, and an automatic analytical device configured to implement said method - Google Patents
A method for quantifying an analyte, and an automatic analytical device configured to implement said method Download PDFInfo
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- CN106062564A CN106062564A CN201480070207.4A CN201480070207A CN106062564A CN 106062564 A CN106062564 A CN 106062564A CN 201480070207 A CN201480070207 A CN 201480070207A CN 106062564 A CN106062564 A CN 106062564A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
- G01N33/54326—Magnetic particles
- G01N33/54333—Modification of conditions of immunological binding reaction, e.g. use of more than one type of particle, use of chemical agents to improve binding, choice of incubation time or application of magnetic field during binding reaction
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
- G01N33/54326—Magnetic particles
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/743—Steroid hormones
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/82—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving vitamins or their receptors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
- G01N35/025—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations having a carousel or turntable for reaction cells or cuvettes
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
- G01N35/04—Details of the conveyor system
- G01N2035/0439—Rotary sample carriers, i.e. carousels
- G01N2035/0446—Combinations of the above
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
- G01N35/04—Details of the conveyor system
- G01N2035/046—General conveyor features
- G01N2035/0465—Loading or unloading the conveyor
Abstract
The present invention deals with a novel method for determining the amount of an analyte in a sample comprising an initial purification step, occurring in a first container, comprising the following steps of mixing the sample, a delipidation agent and magnetic particles coated with first analyte binding partners in the first container, incubating the mix, removing the unbound reagents from the mix, and eluting the bound analyte in an elution solution; a transferring step consisting transferring in a volume of the elution solution comprising the analyte from the first container to a second container; and a quantification step, occurring in the second container, consisting of quantifying the analyte in said elution solution.
Description
Technical field
The present invention relates to the novel method of the amount of a kind of analyte for determining in sample, relate more specifically to a kind of profit
With the method for immunoassay and the automatic analysing apparatus being configured to enforcement the method.
Background technology
The present invention relates to a kind of for quantifying the method for the amount of analyte present in sample, in particular so that can quantify
Analyte and without carrying out the method that complicated laborious Sample Purification on Single analyzes the last stage in advance.
The method that the invention still further relates to determine the amount for the analyte diagnosed the illness.
Simplification extraction and separation method are the key features of improved method.Require that being individually purified step can significantly extend
Time of the method, and owing to there is the step of at least one manual operation sample, the most only possible draw when determining concentration
Enter potential error, and the trackability of sample may be made to produce potential error.
Removing compound (such as, lipid) from sample and usually need settling step, settling step needs much manually behaviour
Make and centrifugation.A step in the analyte purification step carried out before quantization may need to use organic solvent, has
Machine solvent can be poisonous and may need evaporation equipment, and evaporation equipment uses very inconvenient in clinical biochemical laboratory.
Summary of the invention
It is contemplated that overcome the problem associated with existing method.
Therefore, the present invention meets the demand to a kind of simple effective method for quantifying the analyte in sample.Its
Manually handle based on eliminating the complicated of defat-extraction-purification.The present invention has been achieved with making it possible to be substantially reduced the deadline
Method, the method is more more effective than method before, the most more cost effective, and allows to follow the trail of completely all operations, therefore
It is more suitable for the conventional use of clinical laboratory.
The present invention based on the finding that, i.e. single step purification (wherein, in same container biased sample, degreasing agent and point
Analysis thing binding partners) effectively work.
So, in first aspect, a kind of method that the present invention relates to analyte for quantifying in sample, including:
-initial purification steps, occurs in the first container, comprises the following steps:
A) biased sample, degreasing agent and be coated with the first magnetic of the first analyte binding partners in the first container
Grain,
B) mixture in incubation accommodates the first container, comprises in sample with the lipid included in deposit sample making
Analyte is bound to the first analyte binding partners,
C) the first container is placed in magnetic field, the first magnetic-particle to be attracted to by magnetic force the inner wall part of the first container
Point,
D) mixture accommodated from the first container removes unconjugated reagent,
E) in eluting solution the analyte of elution of bound so that analyte is separated with the first analyte binding partners,
-transfer step, comprises the following steps:
F) the first container is placed in magnetic field, the first magnetic-particle to be attracted to by magnetic force the inner wall part of the first container
Point,
G) the eluting solution including analyte of certain volume is transferred to second container from the first container, and
-quantization step, this step occurs in second container, by the step group of the analyte quantified in described eluting solution
Become.
The present invention can be used for the aqueous Biomedia of any mankind, such as blood, serum or blood plasma.
According to aspects of the present invention, in the first container and second container at least one for cuvette (cuvette,
Cuvette), test tube or similar vessel.Each in first container and second container can be cuvette, examination
Pipe or similar vessel.
According to aspects of the present invention, at least one in the first container and second container is made up of glass or plastics.First
Each of which in container and second container can be made up of glass or plastics.
Described transfer step can use such as sampling and the instrument of liquid-transfering device (pipetting device, liquid sucking device)
Carry out.
According to an aspect of the present invention, incubation step includes sample defatting step.
It should be noted that, it is advantageous to degreasing agent is advantageously configured to the lipid precipitation included in beneficially sample.
Degreasing agent can be polyanion analyte, such as dextran sulfate, phosphotungstic acid, or heparin (exists II race sun
In the case of ion, such as magnesium, manganese or calcium).
This incubation with degreasing agent allows lipid precipitation (due to degreasing agent), and allows to be coated with on analyte and magnetic-particle
The the first analyte binding partner binds covered.
According to aspects of the present invention, removing step includes that washing step, washing step include utilizing wash solution washing the
One magnetic-particle.
In certain aspects of the present disclosure, by by alkaline solution (basic solution), (such as NaOH, such as 0.3N are extremely
0.6N NaOH) add the first container of the analyte including combination and form eluting solution.Then, solution will be neutralized (such as,
Citric acid, more specifically 0.3 to 0.6M citric acid) and method buffer add in the first container.
At the aspect particularly of the present invention, method buffer is included in the BSA in MOPS buffer, polypep, manna
Alcohol, sucrose, triton-antioxidant blends, sodium ascorbate, trolox and sodium bicarbonate.
According to aspects of the present invention, shifting liquid instrument can be used to add in the first container and second container and hold from first
Device and second container remove any liquid (reagent in solution, buffer, wash solution etc.).
According to an aspect of the present invention, analyte can be any vitamin D metabolism thing, more preferably 1,25-dihydroxy
Base vitamin D (1,25D), or steroid (such as aldosterone, androgen, estrogen, progestogen or cholesterol).Vitamin D generation
Thanking to thing can also be 25-hydroxy-vitamin D, such as 25-hydroxy-vitamin D2Or 25-hydroxy-vitamin D3。
According to a preferred aspect of the present invention, analyte is 1,25-dihydroxyvitamin D (1,25D).This analyte is at blood
In concentration the lowest, and owing to its normal concentration is 10 to 100 slight grams per milliliters (picogrammes/ml (piks/in the least
Rise)), therefore its mensuration has challenge very much.
In human blood 1, the concentration of 25D can very well indicate the metabolic effectiveness of human body vitamin D, and
Chronic nephropathy can be indicated well.
Being difficult to be developed for determining 1, the method for 25D level, this is primarily due in blood 1, and the concentration of 25D is non-
The lowest.
It is known that in automated system or before utilizing manual methods to be analyzed, need the most repeatedly to carry
Take step to measure 1,25D.Nowadays available on market existing extracting method needs large number quipments, including purification column, rotator,
Centrifugal separator and nitrogen vaporizer.Usually need solvent.The positive identification of sample can be impaired.
The quantization of analyte can be carried out by any technology well known to the skilled artisan in the art.The present invention relates to generally
For the technology of analyte quantification below and:
-clinical chemistry or biochemical test, this test uses serum or other aqueous Biomedia to carry out, and wherein profit
Measuring principle be substantially spectrophotography；
-immunoassay, are carried out according to different technical methods (such as, ELISA, EIA), measure by spectrophotography,
Fluorescence or CLIA (by luminescence) are carried out.
In certain aspects of the present disclosure, carry out analyte quantification by immunoassay, utilize the second analyte binding partners
Carry out described immunoassay.
In certain aspects of the present disclosure, in the first analyte binding partners and the second analyte binding partners at least
A kind of (and each in the such as first analyte binding partners and the second analyte binding partners) can be many grams
Grand antibody, monoclonal antibody, chimeric antibody, through engineering approaches or humanized antibody, scFV or Fab fragment.
In certain aspects of the present disclosure, the first analyte binding partners and the second analyte binding partners are identical
Or it is different.
It is by competition binding method for quantifying one of method for optimizing of analyte present in low concentration sample.When dividing
Analysis thing be little molecule and do not have multiple combination probability time, need this competition binding method.Suitably competition binding method
Take various forms, and be well known to those skilled in the art.Typical competition binding method will include making analyte tie
The sample closing the unmarked form that gametophyte comprises same analyte with the mark pattern of analyte and suspection contacts.
Be found indicates the unmarked analysis in sample with the amount of the labelled analyte of analyte binding partner binds
The ratio of thing.Alternatively, competition binding method can include providing the analyte being combined with the mark pattern of analyte to combine spouse
Body, the sample of the analyte that suspection comprises unmarked form adds to analyte binding partners, and measures what instruction existed
The amount being replaced labelled analyte of the amount of unmarked analyte.
More specifically with preferred aspect, the method for the present invention can be carried out in full automatic mode.According to this
Bright preferred aspect, method is carried out by automatic analysing apparatus, and such as Active immunity measures analyser.
The intrinsic innovation of the method is to analyze last stage full automation in same instruments, and non-manual carry out or
Carry out on the equipment separated.
In one aspect of the invention, it is provided that, move liquid, incubation and blend step by automatic analysing apparatus management and control.
The invention further relates to a kind of automatic analysing apparatus being configured to implement the method according to the invention, more specifically
Relate to a kind of automatic analysing apparatus, comprising:
-multiple containers,
-rotor, has generally vertical rotation axis and to rotate about axis the most driven, and this rotor defines
The radially outward chamber of opening,
-loading attachment, its intracavity being suitable to container is loaded in rotor,
-at least one sampling and liquid-transfering device, is suitable to provide reagent and sample to the container of the intracavity being contained in rotor,
The sedimentation of-magnetic and wash module, be suitable to the accommodating container taken out in rotor and generate magnetic field, and magnetic settles and washes
Wash module and include being suitable to the pipettor tool of the container draw fluid in being contained in magnetic sedimentation and wash module,
-magnetic attracts module, also referred to as Magnetic Isolation module, including being suitable to the accommodating container taken out in rotor upwards
Open enclosure, and it is positioned at the first magnetic field generator near upward opening shell, and
-quantify device, be suitable to the accommodating container taken out in rotor and analyte that the container contents to described taking-up is received
Quantify,
Wherein, sampling and liquid-transfering device are suitable to turn the solution of certain volume from the container being contained in magnetic attracts module
Move to other container being contained in rotor.
Therefore, the analyte the most having utilized eluting solution to make the first container contents receive separates with magnetic-particle, and rotor is just
First container moving into magnetic and attracts module, magnetic attracts module that the magnetic-particle that the first container contents is received is attracted to first
The inwall of container.Then, sampling and liquid-transfering device draw the eluting solution of the nonmagnetic granule of certain volume from the first container, and
The eluting solution of this volume is dispensed into the second container being contained in rotor.
This second container is specifically designed to the analyte quantified in solution.The concentration of the analyte in eluting solution passes through ability
Method (such as, competition binding method) known to the technical staff in territory is measured, when the molecule of analyte is the least and without multiple
In conjunction with probability time, need to use competition binding method.Suitably competition binding method takes various forms, and is in this area
Technical staff known to.
If the equipment for drying that automatic analysing apparatus includes being configured to controlling automatic analysing apparatus in one aspect of the invention and
Module is to implement the control unit of the method according to the invention.
In one aspect of the invention, the first magnetic field generator is positioned at the side of upward opening shell.
In one aspect of the invention, the first magnetic field generator is configured to along the container being contained in upward opening shell
Sidewall sections extends.
In one aspect of the invention, the first magnetic field generator is configured to the container institute that will be contained in upward opening shell
The magnetic-particle accommodated is attracted to the inner wall section of described container, and advantageously be the inner sidewall part being attracted to container.
In one aspect of the invention, magnetic sedimentation and wash module include that the second magnetic field being arranged to produce magnetic field occurs
Device.
In one aspect of the invention, the container that pipettor tool is suitable in being contained in magnetic sedimentation and wash module provides
Wash solution.
In one aspect of the invention, at least one sampling and liquid-transfering device are suitable for the container being contained in rotor provides
Alkaline solution and method buffer and neutralize solution.
In one aspect of the invention, at least one sampling and liquid-transfering device are suitable in being contained in magnetic attraction module
The eluting solution comprising analyte of certain volume drawn by container, and be dispensed into by the eluting solution of this volume and be contained in rotor
Other container.
In one aspect of the invention, at least one sampling and liquid-transfering device are suitable to from the first memory area and the second storage
Area sampling sample to be analyzed and reagent, and gained sampling is transferred to be positioned at the container of the intracavity of rotor.
In one aspect of the invention, magnetic attracts module to be positioned at above waste canister.
In one aspect of the invention, upward opening shell is outside and inwardly open, and the most outwardly and inwardly
Opening.
In one aspect of the invention, the analyte that device is configured to measure or determine that the container contents of taking-up receives is quantified
Amount, such as concentration.
In one aspect of the invention, quantify device to be configured through combining mensuration (such as, immunoassay or competition binding
Measure) measure or determine the amount of analyte, such as concentration.
In one aspect of the invention, quantifying device is for development and to read luminous luminometer.Quantify device can wrap
Include the light tight room being suitable to the accommodating container taken out from rotor, and be suitable to the luminous photomultiplier tube quantifying to produce.
Accompanying drawing explanation
Referring now to accompanying drawing, the present invention is described in detail further, in the accompanying drawings:
Fig. 1 is the perspective view according to automatic analysis apparatus of the present invention.
Fig. 2 is the fragmentary, perspective view of the automatic analysing apparatus in Fig. 1.
Fig. 3 is the fragmentary, perspective view of the automatic analysing apparatus in Fig. 1.
Fig. 4 is the diagram of the method illustrating the amount for determining the analyte in sample according to the present invention.
Detailed description of the invention
Fig. 1 to 3 depicts the automatic analysing apparatus 2 of the amount for determining the analyte in sample according to the present invention.
Automatic analysing apparatus 2 includes the Part I 3 for storing reagent and sample to be analyzed, and be used for measuring and
The Part II 4 analyzed.Part I 3 includes the first memory area 3a, and it is suitable to accommodating sample box 5, and each sample box is equal
Including sample carrier 5a and the sample reservoir 5b being positioned on sample carrier 5a；With the second memory area 3b, it is suitable to house
Test kit 6, each test kit all includes reagent carrier 6a and the reagent reservoirs 6b being positioned on reagent carrier 6a.Sample is store
The sample accommodated in storage can be blood sample, serum or blood plasma.The reagent accommodated in reagent reservoirs can be that eluting is molten
Liquid, neutralization solution, buffer, degreasing agent, or comprise scion grafting (grafted, grafting) or be coated with analyte binding partners
The solution of magnetic-particle, such as, comprise the molten of magnetic nanoparticle by the antibody functionalization corresponding with analyte to be quantified
Liquid.
Automatic analysing apparatus 2 farther includes rotor or conveyer belt 7, rotor or conveyer belt have generally vertical rotary shaft
Line and axis can be rotated about driven by motor (not shown) rotatably.Rotor 7 defines the chamber 8 of radially outward opening.
Automatic analysing apparatus 2 farther includes loading attachment 9, and loading attachment is suitable to store transparent reaction small container 11 and incite somebody to action
Described transparent reaction small container 11 is loaded in the chamber 8 of rotor 7.
Automatic analysing apparatus 2 also includes that sampling and liquid-transfering device 13, sampling and liquid-transfering device are suitable to deposit from being contained in first
Sampling reagent in sample in sample box 5 in the 3a of storage area territory, and the test kit 6 in being contained in the second memory area 3b.
Sampling and liquid-transfering device 13 are further adapted for little to sample and the reagent distribution transparent reaction in the chamber 8 being contained in rotor 7 of sampling
In container 11.
Specifically, sampling and liquid-transfering device 13 include the sampling head 14 with sampling needle 15.Sampling and liquid-transfering device 13
Farther include the first supporting member 16 that can move along the first horizontal direction D1 relative to the housing of automatic analysing apparatus 2, with
And supported by the first supporting member 16 and can be relative to the first supporting member 16 along second water orthogonal with the first horizontal direction D1
Square the second supporting member 17 moved to D2.Sampling head 14 is supported by the second supporting member 17, and can be relative to second
Support component 17 vertically D3 moves.
Sampling and liquid-transfering device 13 farther include to be suitable to make the first supporting member 16 shift along the first horizontal direction D1
First shifting tool 18, be suitable to the second shifting tool 19 of making the second supporting member 17 shift along the second horizontal direction D2, and
Be suitable to the 3rd shifting tool 21 making sampling head 14 vertically D3 shift.
Advantageously, sampling head 14 is suitable to make sampling needle 15 swing.This makes when sampling needle 15, and to be positioned at transparent reaction little
Time in container 11 can mixed transparent reaction small container 11 content.
Automatic analysing apparatus 2 farther include at least one or more relative to rotor 7 radial directed magnetic settle and
Wash module 23.Each magnetic sedimentation and wash module 23 all include settlement section 24, its have be arranged for generate magnetic
The magnetic field generator of field, such as permanent magnet or electric magnet；And pipettor tool 25, it is provided for from being positioned at settlement section
Transparent reaction small container 11 in 24 removes liquid contents, and wash solution is introduced described transparent reaction small container 11
In.
Automatic analysing apparatus 2 also includes the first linear actuators (not shown), and each first linear actuators is all and magnetic
Property sedimentation associate with wash module 23.Each first linear actuators is adapted to take from rotor 7 in centrifugal radial is moved
Go out transparent reaction small container 11, and the transparent reaction small container 11 of taking-up is positioned at respective magnetic sedimentation and wash module 23
Magnetic field generator side.
Therefore, when the transparent reaction comprising the magnetic-particle being coated with analyte binding partners small container 11 is positioned at
Time in magnetic sedimentation and washing station 23, the magnetic that corresponding magnetic field generator will accommodate in described transparent reaction small container 11
Grain is attracted to the inner wall section of transparent reaction small container 11, and except magnetic-particle and the analyte that is combined with described magnetic-particle
Outside, other content of transparent reaction small container 11 can be pumped to the sedimentation of described magnetic and washing station 23 by pipettor tool 25
Outside.Then, to wash magnetic-particle in wash solution is introduced transparent reaction small container 11 by pipettor tool.One scheduled time
After, described wash solution is pumped to outside by pipettor tool 25.Once transparent reaction small container 11 is through processing, and it will pass through
The centripetal motion of the first linear actuators associated with the sedimentation of described magnetic and wash module is guided on rotor 7 again.
Automatic analysing apparatus 2 farther includes magnetic and attracts module 26, also referred to as Magnetic Isolation module, and it is relative to rotor
7 radial directed are also positioned near sampling and liquid-transfering device 13.Magnetic attracts module 26 to include: housing, which defines and is suitable to house
From the upward opening shell 27 of the transparent reaction small container 11 that rotor 7 takes out；And magnetic field generator 28, such as permanent magnet or
Electric magnet, is arranged on housing and is positioned near upward opening shell 27.Automatic analysing apparatus 2 includes the second linear actuators
(not shown) and magnetic attract module 26 to associate, and are suitable to transparent reaction small container 11 in centrifugal radial is moved from rotor 7
The transparent reaction small container 11 of taking-up is also positioned in upward opening shell 27, i.e. near magnetic field generator 28 by middle taking-up.Have
Profit, upward opening shell 27 is also radially outwardly and inwardly opening.
It should be noted that sampling and liquid-transfering device 13 are suitable in the upward opening shell 27 being contained in magnetic attraction module 26
Transparent reaction small container 11 is sampled the content of certain volume, and the content of described volume is distributed be contained in rotor 7
In interior transparent reaction small container.
Therefore, when the transparent reaction comprising eluting solution, analyte and magnetic-particle small container 11 being positioned at magnetic suction
When drawing in module 26, the magnetic-particle accommodated in described transparent reaction small container 11 is attracted to by corresponding magnetic field generator 28
The inner wall section of bright reaction small container 11, and besides the magnetic particles, other content of transparent reaction small container 11 is adopted
Sample and liquid-transfering device 13 aspirate and distribute to other the transparent reaction small container 11 being contained in rotor 7.
Preferably, magnetic attracts module 26 to be positioned at above waste canister, and is arranged so that when there being transparent reaction small container
11 when being newly introduced in upward opening shell 27, described in the transparent reaction that will introduce before of the transparent reaction small container 11 that is newly introduced
It is outside that small container 11 is pushed into upward opening shell 27.Then, the described transparent reaction small container 11 promoted is under gravity
Fall in waste canister.
The quantization dress of the analyte that automatic analysing apparatus 2 accommodates in farther including to be suitable to quantify transparent reaction small container 11
Put 29.Quantify device 29 be preferably used for development and read the luminometer of luminescence.It should be noted that quantization device 29 can include
Be suitable to the light tight room 31 of the accommodating transparent reaction small container 11 taken out from rotor 7, and known to be suitable to quantify to produce
The photomultiplier tube (not shown) of luminous quantity.The concentration of analyte to be measured is depended in this measurement.Once complete measure, transparent instead
Answer small container 11 to will pass through the motion quantifying the linear actuators provisioned in device 29 to be removed from quantization device 29, and removed
Move in waste canister.
Automatic analysing apparatus 2 also includes said apparatus and the control unit of module being configured to control automatic analysing apparatus 2
31。
Automatic analysing apparatus 2 farther include rinse and cleaning system (not shown), its be suitable to rinse and clean-up sampling and
The sampling needle 15 of liquid-transfering device 13.
Fig. 4 depicts the method for the amount for determining the analyte in sample according to the present invention.Described method is by basis
Automatic analysis apparatus of the present invention 2 is carried out.
The method of the amount for determining the analyte in sample according to the present invention comprises the following steps:
Mix in-utilization sampling and the liquid-transfering device 13 first transparent reaction small container 11 in being contained in rotor 7 and comprise
The sample of analyte 33 to be quantified, degreasing agent 34 and be coated with the first analyte binding partners 36 magnetic-particle 35
One solution (step S1)；
-utilize the interior mixture accommodated of rotor 7 incubation the first transparent reaction small container 11 so that lipid is because of degreasing agent 34
Precipitate, and analyte 33 is combined (step S2) with the first analyte binding partners 36；
-utilize rotor 7 to be carried by first cuvette 11 before magnetic sedimentation and wash module 23；
-from rotor 7, take out the first transparent reaction small container 11 and described first transparent reaction small container 11 is positioned at
Near the magnetic field generator of the sedimentation of described magnetic and wash module 23, in order to magnetic-particle 35 is attracted to the by its magnetic field generator
The inner wall section of one transparent reaction small container 11；
-utilize the pipettor tool 25 of magnetic sedimentation and wash module 23 to aspirate unconjugated from the first cuvette 11
Reagent (step S3)；
-utilize pipettor tool 25 to introduce in transparent reaction small container 11 by wash solution, to wash magnetic-particle；
-utilize pipettor tool 25 to aspirate wash solution from the first cuvette 11；
-the first the most scrubbed transparent reaction small container 11 is reloaded in rotor 7；
-utilize sampling and liquid-transfering device 13 to provide eluting solution in the first transparent reaction small container 11, with elution of bound
Analyte, will analyte 33 separate (step S4) with magnetic-particle 35；
-utilize rotor 7 to be carried by first cuvette 11 before magnetic attraction module 26；
-from rotor 7, take out the first transparent reaction small container 11 and described first transparent reaction small container 11 is positioned at
In magnetic attracts module 26 so that magnetic-particle 35 is attracted in the first transparent reaction small container 11 by its magnetic field generator 28
Wall part；
-utilize sampling and liquid-transfering device 13 to aspirate eluting solution and analyte (step from the first transparent reaction small container 11
Rapid S5)；
-utilize sampling and liquid-transfering device 13 eluting solution and analyte 33 to be distributed to the second sky being contained in rotor 7
In transparent reaction small container 11' (step S6)；
-utilization sampling and liquid-transfering device 13 provide to comprise to the second transparent reaction small container 11' and are coated with the second analyte
Second solution (step S7) of the magnetic-particle 37 of binding partners 38；And
-quantify the analyte in the interior eluting solution accommodated of the second transparent reaction small container 11'.
By with reference to following non-limiting and non exhaustive example, the present invention will be described:
Example:
Example 1:Amount according to the 1.25D concentration in measuring samples of the present invention
The mensuration of the 1,25D in human blood can very well be indicated the metabolic effectiveness of health vitamin D.
Being difficult to be developed for determining 1, the assay method of 25D level, this is primarily due in blood 1, and 25D's is dense
Spend the lowest.
It is known that in automated system or before utilizing manual methods to be analyzed, need the most repeatedly to carry
Take step to measure 1,25D.Nowadays available on market existing extracting method needs large number quipments, including purification column, rotator,
Centrifugal separator and nitrogen vaporizer.Usually need solvent.The positive identification of sample can be impaired.
According to the present invention, the 1,25D in sample is measured first from carrying out sample defat in the first cuvette
Carry out sample pretreatment for 1,25D and start.Utilize from 22 μ L, 10g sulfur that Sigma (Sigma) catalog number is D8787
Acid glucosan (50k) carries out defat in one liter of 0.5M magnesium chloride and 218 μ L sample.
Afterwards, 1, the 25D 46 μ L being captured to immediately be combined with 314 μ L optimization substituting agent solution are coated with anti-1, and 25D resists
On the magnetic-particle (MP) of body.Substituting agent reagent is by the 4.035g tri-hypophosphite monohydrate hydrogen dipotassium in 1 liter, 0.489g biphosphate
Potassium, 19.5g sodium chloride, 4.19gANSA, 0.209g warfarin and 104.7mL methanol are constituted.By with every 1 gram
Speedbeads Carboxylate-modified granule 36-144mg antibody conjugate anti-1,25D antibody makes the MP coating anti-1,25D.From
A diameter of 0.8 μm of MP that Thermo Scientific catalog number 45152105050350 obtains.It has been found that make defat sample
Within ten minutes, be enough to capture on granule 1,25D with MP incubation at a temperature of 37 DEG C.
Utilize by 0.6g tri-hypophosphite monohydrate hydrogen dipotassium, 0.97g potassium dihydrogen phosphate, 1.0g sodium chloride, 1.0g tween 20,
1.0g Proclin-300 and 0.1g sodium nitride (IDS catalog number is IS-CW100) are dissolved in the wash solution of 1 liter of water composition to be come
Washing MP.At least need MP is carried out 4 independent washings, the most also need with MOPS buffer (include 231mg MOPS sodium salt,
209mg MOPS and 0.9g Hydrazoic acid,sodium salt) washing, to remove the uncombined thing in reactant mixture and precipitation.
The 0.4N sodium hydroxide utilizing 75 μ l carries out the eluting of 6 minutes to the 1,25D of capture on MP.Then, 25 μ L are utilized
0.4M citric acid and the mensuration buffer of 100 μ L be neutralized step, to produce the basis identical with mensuration caliberator.
120 μ L eluates are transferred to the second cuvette from the first cuvette and carry out 1,25D measurement.
Utilize 1,25-dihydroxyvitamin D to measure reagent (IDS catalog number is IS-2400) and measure 1,25D.By 120
μ L comprises eluate and the biotinylation goat-anti-1,25D antibody incubation of the 1,25D of extraction.Then, adding 1,25D-acridine is conjugated
Thing, conjugate can fight for antibody combining site.Then, add the magnetic-particle of coating streptavidin, and further
Incubation step after, washing magnetic-particle to remove unconjugated material.Add after triggering reagent, flash type chemiluminescence
Reaction starts.By the photomultiplier measurement optical signal as Relative light units (RLU), present in optical signal and sample 1,
The amount of 25D is inversely proportional to.
The method can process the high lipid reaching 3g/dL triglyceride, 300mg/dL cholesterol and 7.55g/dL protein
Sample.Observing, full automatic method has with IDS-iSYS1, the 25D immunity capsule extracting method in example 2 very well
Dependency.
Find, it is possible to use coating anti-1, the magnetic-particle of 25D antibody and optimization extract reagent directly from mankind's blood herein
1,25D is extracted, in addition to using magnetic separator to wash MP, it is not necessary to use multinomial equipment, and can receive from MP in clear
Collection eluate.Whole extraction process needs about 21 minutes.The time drawing the first result is 93 minutes.
Example 2:Amount according to the 1.25D concentration in known method measuring samples before
By adding 500 μ L sample in the glass of tape label or plastic test tube, add 50 μ L degreasing agents afterwards and (include one
Rising 10 grams of dextran sulfates (50k) in 0.5M magnesium chloride, Sigma catalog number is D8787), in test tube, sample is carried out
Defat.Mixing is also centrifuged 15 minutes with 2000g.
Capsule is labelled.Remove capsule nut.150 μ L defat samples are added in the capsule comprising solid suspension liquid,
Solid phase is attached with the monoclonal antibody to 1,25D high special.Make nut return safely.At room temperature capsule is rotated upwardly and downwardly
90 minutes so that 1,25D is combined with monoclonal antibody.
Make upright 3 to 5 minutes of capsule so that gel precipitation.Remove nut and make bottom plug depart from capsule.By each capsule
It is centrifuged 1 minute with 500 to 1000g in being placed on glass or plastic test tube.
Wash capsule with water 3 times, carry out 1 minute incubation every time, be centrifuged 1 minute with 500-1000g afterwards, to remove
Possible interfering material.
Capsule is transferred to the 2mL polypropylene taper of suitable labelling have chance with base tube.The ethanol elution utilizing 150 μ L captures
1,25D tri-time, carry out 1 to 2 minute incubation every time, be centrifuged 1 minute with 500-1000g afterwards.
Abandon capsule.The microtest tube accommodating eluate is placed in heat block or water-bath the temperature with 40 DEG C in gentleness
Nitrogen flow down evaporation 45 to 60 minutes.Each microtest tube is reconstructed with the mensuration buffer of 200 μ L.
Utilize 1,25-dihydroxyvitamin D to measure reagent (IDS catalog number is IS-2400) and measure the immunity of reconstruct
Purification of samples, as described in example 1.
Whole extraction process needs about 4 hours.Show that the time of the first result is of about 5 hours.
Certainly, the present invention is not limited to the embodiment described above by limiting examples, and on the contrary, the present invention comprises
Its all embodiments.
Claims (18)
1. for the method determining the amount of the analyte in sample, including:
-purification step, comprises the following steps:
A) by sample, degreasing agent and be coated with the first magnetic-particle of the first analyte binding partners in the first container mixed
Close,
B) mixture that the first container contents described in incubation is received, to precipitate the lipid comprised in described sample and to make in described sample
The analyte comprised and described first analyte binding partner binds,
C) described first container is placed in magnetic field, described first magnetic-particle is attracted to described first container by magnetic force
Inner wall section,
D) the described mixture accommodated from described first container removes unconjugated reagent,
E) analyte of elution of bound in eluting solution, so that described analyte is divided with described first analyte binding partners
From,
-transfer step, comprises the following steps:
F) described first container is placed in magnetic field, described first magnetic-particle is attracted to described first container by magnetic force
Inner wall section,
G) the described eluting solution including described analyte of a volume is transferred to second container from described first container, and
-quantization step, described quantization step occurs in described second container, and described quantization step is by quantifying described analyte
Step forms.
Method the most according to claim 1, wherein, described analyte is vitamin D metabolism thing or steroid.
Method the most according to claim 2, wherein, described analyte is 1,25-dihydroxyvitamin D (1,25D) or 25-
Hydroxy-vitamine D.
Method the most according to claim 2, wherein, described analyte be from by aldosterone, androgen, estrogen, pregnant swash
The steroid selected in the group of element and cholesterol composition.
Method the most according to any one of claim 1 to 4, wherein, described sample is aqueous Biomedia.
Method the most according to any one of claim 1 to 5, wherein, utilizes immunoassay to complete described analyte
Quantify.
Method the most according to claim 6, wherein, utilizes the second magnetic being coated with the second analyte binding partners
Grain carries out described immunoassay.
8. according to method in any one of the preceding claims wherein, wherein, described first analyte binding partners and described
At least one in second analyte binding partners is polyclonal antibody, monoclonal antibody, chimeric antibody, through engineering approaches or people source
Change antibody, scFV or Fab fragment.
9. according to method in any one of the preceding claims wherein, wherein, described degreasing agent is polyanion analyte.
Method the most according to claim 9, wherein, in the case of there is II race cation, described degreasing agent be from by
The polyanion analyte selected in the group of dextran sulfate, phosphotungstic acid and heparin composition.
11. according to method in any one of the preceding claims wherein, and wherein, the step of described removing includes washing step, institute
State washing step to include utilizing wash solution to wash described first magnetic-particle.
12. according to method in any one of the preceding claims wherein, wherein, molten by adding alkalescence in method buffer
Liquid, adds neutralization solution subsequently and obtains described eluting solution.
13. methods according to claim 12, wherein, described alkaline solution is the NaOH of 0.3N to 0.6N.
14. according to the method described in claim 12 or 13, and wherein, described neutralization solution is the citric acid of 0.3 to 0.6M.
15. according to the method according to any one of claim 12 to 14, and wherein, described method buffer is included in MOPS buffering
BSA, polypep, mannitol, sucrose, triton-antioxidant blends, sodium ascorbate, trolox and bicarbonate in liquid
Sodium.
16. according to the method according to any one of claim 1 to 15, wherein, and described purification step, described transfer step and institute
State quantization step to be implemented by automatic analysing apparatus, such as, measured analyser by Active immunity and implement.
17. 1 kinds of automatic analysing apparatus, including:
-multiple containers (11),
-rotor (7), has generally vertical rotation axis and to rotate about axis the most driven, described rotor (7) boundary
Determine the chamber (8) radially outward opened,
-loading attachment (9), is suitable to be loaded in described container (11) in the described chamber (8) of described rotor (7),
-at least one sampling and liquid-transfering device (13), is suitable to the container in the described chamber (8) being contained in described rotor (7)
(11) reagent and sample are provided,
The sedimentation of-magnetic and wash module (23), be suitable to the accommodating container (11) taken out from described rotor (7) and be suitable to generate magnetic
, the sedimentation of described magnetic and wash module (23) include that the container be suitable in being contained in the sedimentation of described magnetic and wash module is inhaled
Pipettor tool (25) of advection body,
-magnetic attracts module (26), including the upward opening shell being suitable to the accommodating container (11) taken out from described rotor (7)
(27), and it is positioned at the first magnetic field generator (28) near described upward opening shell (27), and
-quantify device (29), be suitable to the accommodating container (11) taken out from described rotor (7) and quantify the container (11) of this taking-up
The analyte of middle receiving,
Wherein, the container (11) that described sampling and liquid-transfering device (13) are suitable to from being contained in described magnetic attracts module (26) is incited somebody to action
The solution of one volume is transferred to another container (11) being contained in described rotor (7).
18. automatic analysing apparatus according to claim 17, wherein, described quantization device (29) is configured through immunity survey
Fixed or competition binding is measured or determines the amount of described analyte.
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| EP13195534.6A EP2881740B1 (en) | 2013-12-03 | 2013-12-03 | A method for quantifying an analyte, and an automatic analytical device configured to implement said method |
| EP13195534.6 | 2013-12-03 | ||
| PCT/EP2014/076367 WO2015082526A1 (en) | 2013-12-03 | 2014-12-03 | A method for quantifying an analyte, and an automatic analytical device configured to implement said method |
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| EP (1) | EP2881740B1 (en) |
| JP (1) | JP6608361B2 (en) |
| CN (2) | CN110609146B (en) |
| AU (1) | AU2014359317A1 (en) |
| BR (1) | BR112016012560A2 (en) |
| CA (1) | CA2932045C (en) |
| DK (1) | DK2881740T3 (en) |
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| CN107110857B (en) | 2015-03-31 | 2019-03-26 | 希森美康株式会社 | Immunoassay apparatus |
| CN106226523A (en) * | 2016-07-04 | 2016-12-14 | 福建广生堂药业股份有限公司 | Detection method, reagent and the detection kit of a kind of immunological marker thing |
| CN105974132A (en) * | 2016-07-04 | 2016-09-28 | 福建广生堂药业股份有限公司 | Detection method, detection reagent and detection kit for alpha-fetoprotein variant |
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Also Published As
| Publication number | Publication date |
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| US20160313315A1 (en) | 2016-10-27 |
| ES2724537T3 (en) | 2019-09-11 |
| AU2014359317A1 (en) | 2016-06-23 |
| US10473653B2 (en) | 2019-11-12 |
| DK2881740T3 (en) | 2019-05-13 |
| CA2932045C (en) | 2023-06-20 |
| JP2016539339A (en) | 2016-12-15 |
| EP2881740A1 (en) | 2015-06-10 |
| CN106062564B (en) | 2020-01-03 |
| CN110609146B (en) | 2023-06-06 |
| JP6608361B2 (en) | 2019-11-20 |
| CN110609146A (en) | 2019-12-24 |
| EP2881740B1 (en) | 2019-02-13 |
| WO2015082526A1 (en) | 2015-06-11 |
| CA2932045A1 (en) | 2015-06-11 |
| BR112016012560A2 (en) | 2017-08-08 |
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